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MRI: a flexible and widely applicable modality in drug discovery

18 October 2012

MRI methods play a wide-ranging role in drug discovery and development. This extremely flexible imaging modality is now widely used for in vivo profiling of potential drug candidates in animal models, provides an increasing choice of physiological structure and function markers applicable in clinical development and even has a role in the in vitro optimization of controlled release drug formulations. MRI has particular utility for translational biomarkers, where the same spin physics is used to interrogate the same biological parameter, in the same way, in both animals and humans.

n this issue of Drug Discovery Today, Editor’s Choice, I highlight four recent articles that address the variety of ways in which MRI is impacting drug discovery and development.

The drug discovery process begins with the evaluation of potential new medicines in preclinical species. Rotman et al. survey optical and MRI techniques applicable to mouse models of Alzheimer’s disease. The high-resolution optical approaches are complemented by MRI methods, which enable full brain coverage and have substantial translational potential because MR techniques available for use in clinical trials can be back-translated to animal scanners. Treatment effects observed in the murine models can then generate specific hypotheses to be tested in clinical development. MRI measures of gross brain atrophy (from structural images), synaptic efficiency (from task-free fMRI), white matter connectivity (from diffusion tensor imaging) and resting perfusion (from arterial spin labeling) are all tractable in clinical studies and can be implemented preclinically providing a strong translational link.

One of the more challenging MRI methods to apply in the clinical drug development setting is functional MRI (fMRI) to assess pharmacological effects on brain function. These challenges arise due to the complexity of the technique, the need for specialized equipment and expertise and the fact that to date the method is currently not well supported by commercial imaging contract houses. Comprising a diverse set of collaborators from industry and academia, my co-workers and I bring together industry processes and expectations with the constraints and complexity of fMRI and propose “good imaging practice” guidelines to help the execution of industry-sponsored pharmacological fMRI studies. This includes specific guidelines and checklists to ensure complete and appropriate study planning. This article was the first of two companion articles on this topic recently published in Drug Discovery Today.

Since the discovery of MRI methods in the 1970s, there has been a general trend toward increasing static magnetic field strengths. 1.5T scanners were the norm 10–15 years ago and, while still prevalent, an increasing number of 3T scanners are available and in use in clinical trials – indeed, they are currently preferred for many of the emerging MRI techniques mentioned above. Looking to the future, Luijten and Klomp provide an introduction to the possibilities of MRI scanners with ‘ultra high field’ strengths of 7T and above. A number of such systems are now operating in high-end research centers, and are providing unprecedented spatial resolution and image contrast in the living human organism. This translates to improved detection of demyelinating white matter lesions in multiple sclerosis and vascular pathologies, as well as improved sensitivity and specificity of spectra.

Finally, MRI techniques can be applied in vitro to study the physic-chemical properties of oral drug formulations (the capsules or tablets) themselves, as reviewed by Dorozynski et al. The behavior of controlled release dosage forms during hydration and dissolution conditions is of particular interest, and can be monitored using a variety of MRI sequences and parameters. This is of increasing importance in the development of appropriate formulations for oral medicines.

Biography

Adam Schwarz received a Bachelor of Science with First Class Honors in Physics (1991) and a PhD in Electrical and Electronic Engineering (1995) from the University of Canterbury, New Zealand. Following imaging physicist positions at the Institute of Cancer Research (London, UK) and Marconi Medical Systems (Farnham, UK), he joined the pharmaceutical industry where he has worked as an imaging specialist since 2002. Following 5 years with GlaxoSmithKline (Verona, Italy) he joined Eli Lilly and Company (Indianapolis, USA) in 2007, where he has driven the validation and application of imaging methods to drug development across therapeutic areas and clinical phases. He is an author on over 50 scientific articles, 2 books and 4 book chapters. He is a long-standing member of the Institute of Physics and actively involved in the scientific community via committees and consortia including Alzheimer’s Disease Neuroimaging Initiative (ADNI), Campaign Against Major Diseases (CAMD), International Society for Magnetic Resonance in Medicine (ISMRM) and several Innovative Medicines Initiative (IMI) initiatives.

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